Pyrazole-amine compounds useful as kinase inhibitors

ABSTRACT

The present invention provides pyrazole derived compounds of formula (I) 
                         
useful for treating p38 kinase-associated conditions, where G, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and m are as defined herein. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention useful for treating p38 kinase-associated conditions, and methods of inhibiting the activity of p38 kinase in a mammal.

RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.10/837,778, filed May 3, 2004, which claims the benefit of U.S.Provisional Application Ser. No. 60/467,029, filed May 1, 2003. Each ofthe priority applications are incorporated by reference in theirentireties.

FIELD OF THE INVENTION

This invention relates to pyrazole derived compounds useful for treatingp38 kinase-associated conditions. The invention further pertains topharmaceutical compositions containing at least one compound accordingto the invention useful for treating p38 kinase-associated conditions,and methods of inhibiting the activity of p38 kinase in a mammal.

BACKGROUND OF THE INVENTION

A large number of cytokines participate in the inflammatory response,including IL-1, IL-6, IL-8 and TNF-α. Overproduction of cytokines suchas IL-1 and TNF-α are implicated in a wide variety of diseases,including inflammatory bowel disease, rheumatoid arthritis, psoriasis,multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease,and congestive heart failure, among others [Henry et al., Drugs Fut.,Vol. 24 (1999), at pp. 1345-54; Salituro et al., Curr. Med. Chem., Vol.6 (1999), at pp. 807-823]. Evidence in human patients indicates thatprotein antagonists of cytokines are effective in treating chronicinflammatory diseases, such as, for example, monoclonal antibody toTNF-α (Enbrel) [Rankin et al., Br. J. Rheumatol., Vol. 34 (1995), at pp.334-42], and soluble TNF-α receptor-Fc fusion protein (Etanercept)[Moreland et al., Ann. Intern. Med., Vol. 130 (1999), at pp. 478-86].

The biosynthesis of TNF-α occurs in many cell types in response to anexternal stimulus, such as, for example, a mitogen, an infectiousorganism, or trauma. Important mediators of TNF-α production include themitogen-activated protein (MAP) kinases, a family of Ser/Thr proteinkinases that activate their substrates by phosphorylation. The MAPkinases are activated in response to various stress stimuli, includingbut not limited to proinflammatory cytokines, endotoxin, ultravioletlight, and osmotic shock.

One important MAP kinase is p38 kinase, also known as cytokinesuppressive anti-inflammatory drug binding protein (CSBP) or IK.Activation of p38 requires dual phosphorylation by upstream MAP kinasekinases (MKK3 and MKK6) on threonine and tyrosine within a Thr-Gly-Tyrmotif characteristic of p38 isozymes. There are four known isoforms ofp38, i.e., p38-α, p38β, p38γ, and p38δ. The α and β isoforms areexpressed in inflammatory cells and are key mediators of TNF-αproduction. Inhibiting the p38α and β enzymes in cells results inreduced levels of TNF-α expression. Also, administering p38α and βinhibitors in animal models of inflammatory disease has established theeffectiveness of p38 inhibitors in treating those diseases. The presentinvention provides pyrazole derived compounds, useful as kinaseinhibitors, in particular, as inhibitors of p38 kinase.

DESCRIPTION OF THE INVENTION

The present invention pertains to methods of treating p-38 associatedconditions, by administering compounds having the formula (I), and/orpharmaceutically acceptable salts of solvates thereof.

Additionally, according to another aspect of the invention, there areprovided pyrazole derived compounds of formula (I)

useful for treating p38 kinase-associated conditions, where G, X, R₁,R₂, R₃, R₄, R₅, R₆ and m are as defined herein.

According to one aspect of the invention, there is provided pyrazolederived compounds of formula (I),

-   -   wherein G is phenyl or pyridyl;    -   R₁ is hydrogen, alkyl, substituted alkyl, aryl, substituted        aryl, heteroaryl, substituted heteroaryl, cycloalkyl,        substituted cycloalkyl, heterocyclo or substituted heterocyclo,        or C(═O)R₁₈;    -   R₂ is hydrogen, hydroxyl(alkyl), alkoxy(alkyl), haloalkyl,        halogen, cyanoalkyl, alkoxy, substituted alkoxy, or R_(2a),        wherein R_(2a) is C₁₋₆alkyl, amino, alkylamino, substituted        alkylamino, cycloamino, substituted cycloamino, or C₁₋₆alkyl        substituted with one to two of amino, alkylamino, substituted        alkylamino, cycloamino, and/or substituted cycloamino;    -   R₃ is hydrogen, haloalkyl, haloalkoxy, halogen, cyano, nitro,        C₁₋₄alkyl, substituted C₁₋₄alkyl, NR₁₁R₁₂, or OR₁₁;    -   R₄ is hydrogen, C₁₋₄alkyl, substituted C₁₋₄alkyl, halogen,        haloalkyl, haloalkoxy, cyano, nitro, or OR₁₃;    -   R₅ is at each occurrence independently selected from haloalkyl,        haloalkoxy, cyano, nitro, alkyl or substituted alkyl, alkenyl or        substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl        or substituted cycloalkyl, heterocycle or substituted        heterocycle, aryl or substituted aryl, heteroaryl or substituted        heteroaryl, OR₁₃, SR₁₃, S(═O)R₁₄, S(═O)₂R₁₄, P(═O)₂R₁₄,        S(═O)₂OR₁₅, P(═O)₂OR₁₄, NR₁₃R₁₄, NR₁₃S(═O)₂R₁₅, NR₁₃P(═O)₂R₁₄,        S(═O)₂NR₁₃R₁₄, P(═O)₂NR₁₃R₁₄, C(═O)OR₁₃, C(═O)R₁₃, C(═O)NR₁₃R₁₄,        OC(═O)R₁₃, OC(═O)NR₁₃R₁₄, NR₁₃C(═O)OR₁₄, NR₁₆C(═O)NR₁₃R₁₄,        NR₁₆S(═O)₂NR₁₃R₁₄, NR₁₆P(═O)₂NR₁₃R₁₄, NR₁₃C(═O)R₁₄, and/or        NR₁₃P(═O)₂R₁₄;    -   X is —(C═O)NH—, —NH(C═O)—, —NH(C═O)—, —SO₂NH—, —CO₂—, or is        absent;    -   R₆ is hydrogen, alkyl or substituted alkyl, alkoxy or        substituted alkoxy, phenoxy or substituted phenoxy, cycloalkyl        or substituted cycloalkyl, heterocycle or substituted        heterocycle, aryl or substituted aryl, heteroaryl or substituted        heteroaryl; or where X is absent, R₆ can also be selected from        halogen, cyano, trifluoromethyl, alkyl, amino, and/or        alkylamino; or alternatively, R₆ is joined together with a group        R₅ on an adjacent carbon atom to form an optionally-substituted,        fused five to six membered heterocyclic or carbocyclic ring;    -   R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ are independently at each        occurrence selected from hydrogen, alkyl, substituted alkyl,        cycloalkyl or substituted cycloalkyl, heterocycle or substituted        heterocycle, aryl or substituted aryl, and heteroaryl or        substituted heteroaryl, except R₁₅ is not hydrogen;    -   R₁₈ is hydrogen, alkyl or substituted alkyl, alkenyl or        substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl        or substituted cycloalkyl, heterocycle or substituted        heterocycle, heteroaryl, or substituted heteroaryl, aryl or        substituted aryl; and    -   m is 0, 1, 2 or 3;        -   provided that the following compounds are excluded:        -   (A) compounds having the formula (I), wherein R₁ is an            optionally-substituted phenyl, pyridyl, pyridazinyl,            pyrimidinyl, or pyrazinyl ring; R₂ is R_(2a); R₃ is            hydrogen; R₄ is methyl; m is 0; and X—R₆ is            —C(═O)NH(C₁₋₆alkyl), —C(═O)NH(cyclopropyl), or            optionally-substituted oxadiazolyl;        -   (B) compounds having formula (Ix):

-   -   -   -   (i) simultaneously, R₃₀ is trifluoromethyl, R₂ is                methyl, R₃ is hydrogen, R₄ is bromo, X—R₆ is hydrogen,                R_(5b) is hydrogen, and R_(5a) is methyl or

-   -   -   -   (ii) simultaneously, R₃₀ is hydrogen or methoxy, R₂ is                hydrogen or methyl, R₃ is hydrogen, R₄ is hydrogen, X—R₆                is hydrogen, R_(5b) is hydrogen, and R_(5a) is                trifluoromethyl;            -   (iii) simultaneously, R₃₀ is chloro, R₂ is hydrogen, R₃                is hydrogen, R₄ is hydrogen, X—R₆ is cyano, R_(5b) is                hydrogen, and R_(5a) is SR₁₇ wherein R₁₇ is                morpholinylalkyl;            -   (iv) simultaneously, R₃₀ is fluoro, R₂ is methyl, R₃ is                hydrogen, R₄ is hydrogen, X—R₆ is cyano, R_(5b) is                hydrogen, and R_(5a) is N-piperidinyl;            -   (v) simultaneously, R₃₀ is halogen, R₂ is hydrogen or                methyl, R₃ is hydrogen, R₄ is hydrogen, X—R₆ is cyano,                R_(5b) is hydrogen, and R_(5a) is heterocyclo or                substituted heterocyclo;            -   (vi) simultaneously, R₃₀ is chloro, R₂ is                trifluoromethyl, R₃ is hydrogen, R₄ is hydrogen, X—R₆ is                SO₂NH(cycloalkyl), and R_(5a) and R_(5b) are hydrogen;            -   (vii) simultaneously, R₃₀ is hydrogen, R₂ is                trifluoromethyl, R₃ is hydrogen, R₄ is hydrogen, X—R₆ is                hydrogen, R_(5b) is hydrogen, and R_(5a) is substituted                alkyl;            -   (viii) simultaneously, R₃₀ is hydrogen, R₂ is                trifluoromethyl, R₃ is hydrogen, R₄ is methyl, X—R₆ is                hydrogen, R_(5b) is —C(═ONH(alkyl), and R_(5a) is                hydrogen; and            -   (ix) simultaneously, R₃₀ is methoxy, R₂ is methyl, R₃ is                hydrogen, R₄ is methyl, X—R₆ is a                bicyclicheterocyclo(alkyl) or bicyclicheteroaryl(alkyl),                and R_(5a) and R_(5b) are hydrogen; and

        -   (C) compounds having the formula (Iy),

wherein

-   -   -   -   (i) simultaneously, R₂ is hydrogen, R₃ is                trifluoromethyl, R₄ is bromo, X—R₆ is hydrogen, R_(5a)                is trifluoromethyl, and R_(5b) is bromo;            -   and wherein (ii) R₂ is methyl, R₃ is hydrogen, R₄ is                hydrogen, X—R₆ is cyano, R_(5a) is alkoxy, and R_(5b) is                hydrogen.

According to one aspect of the invention, there is provided a method ofusing at least one compound according to formula (I) herein, formodulating a p38 kinase in a mammal, wherein the at least one compoundhas the formula (I),

-   -   wherein G is phenyl or pyridyl;    -   R₁ is hydrogen, alkyl, substituted alkyl, aryl, substituted        aryl, heteroaryl, substituted heteroaryl, cycloalkyl,        substituted cycloalkyl, heterocyclo or substituted heterocyclo,        or C(═O)R₁₈;    -   R₂ is hydrogen, hydroxyl(alkyl), alkoxy(alkyl), haloalkyl,        halogen, cyanoalkyl, alkoxy, substituted alkoxy, or R_(2a),        wherein R_(2a) is C₁₋₆alkyl, amino, alkylamino, substituted        alkylamino, cycloamino, substituted cycloamino, or C₁₋₆alkyl        substituted with one to two of amino, alkylamino, substituted        alkylamino, cycloamino, and/or substituted cycloamino;    -   R₃ is hydrogen, haloalkyl, haloalkoxy, halogen, cyano, nitro,        C₁₋₄alkyl, substituted C₁₋₄alkyl, NR₁₁R₁₂, or OR₁₁;    -   R₄ is hydrogen, C₁₋₄alkyl, substituted C₁₋₄alkyl, halogen,        haloalkyl, haloalkoxy, cyano, nitro, or OR₁₃;    -   R₅ is at each occurrence independently selected from haloalkyl,        haloalkoxy, cyano, nitro, alkyl or substituted alkyl, alkenyl or        substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl        or substituted cycloalkyl, heterocycle or substituted        heterocycle, aryl or substituted aryl, heteroaryl or substituted        heteroaryl, OR₁₃, SR₁₃, S(═O)R₁₄, S(═O)₂R₁₄, P(═O)₂R₁₄,        S(═O)₂OR₁₅, P(═O)₂OR₁₄, NR₁₃R₁₄, NR₁₃S(═O)₂R₁₅, NR₁₃P(═O)₂R₁₄,        S(═O)₂NR₁₃R₁₄, P(═O)₂NR₁₃R₁₄, C(═O)OR₁₃, C(═O)R₁₃, C(═O)NR₁₃R₁₄,        OC(═O)R₁₃, OC(═O)NR₁₃R₁₄, NR₁₃C(═O)OR₁₄, NR₁₆C(═O)NR₁₃R₁₄,        NR₁₆S(═O)₂NR₁₃R₁₄, NR₁₆P(═O)₂NR₁₃R₁₄, NR₁₃C(═O)R₁₄, and/or        NR₁₃P(═O)₂R₁₄;    -   X is —(C═O)NH—, —NH(C═O)—, —NH(C═O)—, —SO₂NH—, —CO₂—, or is        absent;    -   R₆ is hydrogen, alkyl or substituted alkyl, alkoxy or        substituted alkoxy, phenoxy or substituted phenoxy, cycloalkyl        or substituted cycloalkyl, heterocycle or substituted        heterocycle, aryl or substituted aryl, heteroaryl or substituted        heteroaryl; or where X is absent, R₆ can also be selected from        halogen, cyano, trifluoromethyl, alkyl, amino, and/or        alkylamino; or alternatively, R₆ is joined together with a group        R₅ on an adjacent carbon atom to form an optionally-substituted,        fused five to six membered heterocyclic or carbocyclic ring;    -   R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ are independently at each        occurrence selected from hydrogen, alkyl, substituted alkyl,        cycloalkyl or substituted cycloalkyl, heterocycle or substituted        heterocycle, aryl or substituted aryl, and heteroaryl or        substituted heteroaryl, except R₁₅ is not hydrogen;    -   R₁₈ is hydrogen, alkyl or substituted alkyl, alkenyl or        substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl        or substituted cycloalkyl, heterocycle or substituted        heterocycle, heteroaryl, or substituted heteroaryl, aryl or        substituted aryl; and    -   m is 0, 1, 2 or 3;    -   provided that the method does not include administration of        compounds wherein R₁ is an optionally-substituted phenyl,        pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl ring;    -   R₂ is R_(2a); R₃ is hydrogen, R₄ is methyl; m is 0; and X—R₆ is        —C(═O)NH(C₁₋₆alkyl), —C(═O)NH(cyclopropyl), or        optionally-substituted oxadiazolyl.

Further aspects of the invention will be apparent to one skilled in thefield upon reading the disclosure herein.

DEFINITIONS

The following are definitions of terms used in the present specificationand claims. The initial definition provided for a group or term hereinapplies to that group or term throughout the present specification andclaims herein individually or as part of another group, unless otherwiseindicated.

The terms “alkyl” and “alk” refer to a straight or branched chain alkane(hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1to 6 carbon atoms. Exemplary “alkyl” groups include methyl, ethyl,propyl, isopropyl, 1-methylpropyl, n-butyl, t-butyl, isobutyl, pentyl,hexyl, isohexyl, heptyl, dimethylpentyl, diethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. Theterm “C₁-C₄ alkyl” refers to a straight or branched chain alkane(hydrocarbon) radical containing from 1 to 4 carbon atoms, such asmethyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. Alower alkyl is a “C₁-C₄ alkyl.” When alkyl, lower alkyl (or C₁-C₄alkyl)is used as a suffix following another named group, such as“hydroxyalkyl” of hydroxyl(lower alkyl), this is intended to refer to analkyl or lower alkyl (C₁-C₄alkyl) having bonded thereto one, two orthree of the other, specifically-named group(s) at any point ofattachment on either the straight or branched chain of the alkyl. As afurther example, arylalkyl includes groups such as benzyl orphenylethyl. When the term “substituted” is used with such groups, as in“substituted arylalkyl” or “substituted alkoxyalkyl,” it should beunderstood that either the alkyl moiety, the other named moiety, orboth, may be substituted with groups selected from those recited hereinas appropriate, e.g., for the alkyl moiety, groups may be selected fromthose recited below for substituted alkyl, and for the other,specifically-named group, groups may be selected from those recitedbelow for that group.

“Substituted alkyl” refers to an alkyl group as defined abovesubstituted with one or more substituents, preferably 1 to 4substituents, more preferably 1 to 2 substituents, at any availablepoint of attachment on the straight and/or branched chain. Exemplarysubstituents may include but are not limited to one or more of halogen,haloalkyl (e.g., a single halo substituent or multiple halo substituentsforming, in the latter case, groups such as a perfluoroalkyl groupincluding for example, —CHCl₂ and/or CF₃), haloalkoxyl (e.g., includingtrifluoromethoxy), cyano, nitro, alkenyl, alkynyl, cycloalkyl,heterocycle, heteroaryl, aryl, OR_(a), SR_(a), S(═O)R_(e), S(═O)₂R_(e),P(═O)₂R_(e), S(═O)₂OR_(e), P(═O)₂OR_(e), P(═O)(OR)₂, NR_(b)R_(c),NR_(b)S(═O)₂R_(e), NR_(b)P(═O)₂R_(e), S(═O)₂NR_(b)R_(c),P(═O)₂NR_(b)R_(c), C(═O)OR_(a), C(═O)R_(a), C(═O)NR_(b)R_(c),OC(═O)R_(a), C(═O)ONR_(b)R_(c), OC(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(a),NR_(d)C(═O)NR_(b)R_(c), NR_(d)S(═O)₂NR_(b)R_(c),NR_(d)P(═O)₂NR_(b)R_(c), NR_(b)C(═O)R_(a), and/or NR_(b)P(═O)₂R_(e),wherein R_(a), R_(b), R_(c), R_(d) and R_(e) are selected from hydrogen,alkyl, alkenyl, aminoalkyl, alkylaminoalkyl, cycloalkyl(alkyl),aryl(alkyl), heterocyclo(alkyl), heteroaryl(alkyl), cycloalkyl, aryl,heterocyclo, and/or heteroaryl, except R_(e) is not hydrogen; andadditionally, when R_(b) and R_(c) are attached to the same nitrogenatom, they may be joined together to form a cycloamino group. Each ofR_(a), R_(b), R_(c), R_(d) and/or R_(e) on the alkyl and/or cyclicmoieties in turn may be optionally substituted with one to three groups,preferably substituted with up to two groups (0 to 2 groups), selectedfrom lower alkyl, lower alkenyl, R_(f), and a lower alkyl or loweralkenyl substituted with one to two R_(f), wherein R_(f) is selectedfrom one or more of cyano, halogen, haloC₁-C₄alkyl, haloC₁-C₄alkoxy,keto (═O) (where valence allows), nitro, OH, O(C₁-C₄alkyl), SH,S(C₁-C₄alkyl), S(═O)(C₁-C₄alkyl), S(═O)₂(C₁-C₄alkyl), NH₂,NH(C₁-C₄alkyl), N(C₁-C₄alkyl)₂, NH(cycloalkyl), NH(phenyl), phenyl,benzyl, phenoxy, benzyloxy, NHS(═O)₂(alkyl), S(═O)₂NH₂,S(═O)₂NH(C₁-C₄alkyl), S(═O)₂N(C₁-C₄alkyl)₂, S(═O)₂NH(cycloalkyl),S(═O)₂NH(phenyl), C(═O)OH, C(═O)O(C₁-C₄alkyl), C(═O)H,C(═O)(C₁-C₄alkyl), C(═O)NH₂, C(═O)NH(C₁-C₄alkyl), C(═O)N(C₁-C₄alkyl)₂,C(═O)NH(cycloalkyl), C(═O)NH(phenyl), C(═O)NH(phenyl), C(═O)ONH₂,C(═O)ONH(C₁-C₄alkyl), C(═O)ON(C₁-C₄alkyl)₂, C(═O)ONH(cycloalkyl),C(═O)ONH(phenyl), NHC(═O)OC₁-C₄alkyl, N(C₁-C₄alkyl)C(═O)O(C₁-C₄alkyl),NHC(═O)NH₂, NHC(═O)NH(C₁-C₄alkyl), NHC(═O)N(C₁-C₄alkyl)₂,NHC(═O)NH(cycloalkyl), NHC(═O)NH(phenyl), NHC(═O)H, and/orNHC(═O)(C₁-C₄alkyl).

The term “alkenyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least onecarbon-carbon double bond. Exemplary such groups include ethenyl andallyl. Lower alkenyl means an alkenyl group of 2 to 4 carbon atoms.“Substituted alkenyl” refers to an alkenyl group substituted with one ormore substituents, preferably 1 to 4 substituents, more preferably 1 to2 substituents, at any available point of attachment. Exemplarysubstituents may include, but are not limited to, alkyl, substitutedalkyl, and those groups recited above as exemplary substituents forsubstituted alkyl groups.

The term “alkynyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least onecarbon-to-carbon triple bond. Exemplary such groups include ethynyl.“Substituted alkynyl” refers to an alkynyl group substituted with one ormore substituents, preferably 1 to 4 substituents, more preferably 1 to2 substituents, at any available point of attachment. Exemplarysubstituents include, but are not limited to, alkyl, substituted alkyl,and those groups recited above as exemplary substituents for substitutedalkyl groups.

The term “alkoxy” refers to the group OR_(g), wherein R_(g) is selectedfrom alkyl, alkenyl, or cycloalkyl. A C₁-C₄alkoxy is an alkoxy groupOR_(g′) wherein R_(g′) is a C₁-C₄alkyl or C₃-C₄cycloalkyl. A substitutedalkoxy group is an alkoxy group as defined above wherein at least one ofthe alkyl, alkenyl, and/or cycloalkyl moieties is substituted with oneor more, preferably 1 to 4, more preferably 1 to 2, groups selected fromthose recited above for substituted alkenyl groups.

The term “amino” refers to NH₂, and an alkylamino refers to an aminogroup wherein one or both of the hydrogen atoms is or are replaced witha group chosen from alkyl, alkenyl, and/or cycloalkyl. Thus, alkylaminorefers to the group NR_(h)R_(i), wherein R_(h) and R_(i) are selectedfrom hydrogen, alkyl, alkenyl, and/or cycloalkyl, provided R_(h) andR_(i) are not both hydrogen. “Aminoalkyl” refers to an alkyl group asdefined above substituted with an amino group, and an “alkylaminoalkyl”refers to an alkyl group as defined above substituted with one or morealkylamino groups. A substituted alkylamino group is an alkylamino groupwherein at least one of the alkyl, alkenyl, and/or cycloalkyl moietiesis substituted with one or more, preferably 1 to 4, more preferably 1 to2, groups selected from those recited herein as appropriate for therecited moeity. Thus, for example, an optionally-substituted alkylaminogroup refers to the group —NR′R″, wherein R′ and R″ are selected fromhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,cycloalkyl, and substituted cycloalkyl, provided R′ and R″ are not bothhydrogen, as in that case the group is amino and notoptionally-substituted alkylamino.

A cycloamino group refers to a group —NR′R″, wherein R′ and R″ join toform a monocyclic heterocyclo ring, such as, for example, N-morpholinyl,N-piperidinyl, N-piperazinyl and the like. A “substituted cycloamino” isa cycloamino group having one or more, preferably one to 4, morepreferably one to 2, substituents selected from those recited below forsubstituted heterocyclo groups.

The term “alkylthio” refers to the group SR_(g), wherein R_(g) isselected from alkyl, alkenyl, and cycloalkyl. A C₁-C₄alkylthio is analkylthio group SR_(g′) wherein R_(g′) is a C₁-C₄alkyl orC₃-C₄cycloalkyl. A substituted alkylthio group is an alkylthio groupwherein at least one of the alkyl, alkenyl, and/or cycloalkyl moietiesis substituted with one or more, preferably 1 to 4, more preferably 1 to2, groups selected from those recited above for substituted alkenylgroups.

The term “aryl” refers to cyclic aromatic hydrocarbon groups which have1 to 3 aromatic rings, including phenyl and naphthyl. The aryl group mayhave fused thereto a second or third ring which is a heterocyclo,cycloalkyl, or heteroaryl ring, provided in that case the point ofattachment will be to the aryl portion of the ring system. Thus,exemplary aryl groups include,

and so forth.

“Substituted aryl” refers to an aryl group substituted by one or moresubstituents, preferably 1 to 3 substituents, more preferably 1 to 2substituents, at any point of attachment of the aryl ring and/or of anyfurther ring fused thereto. Exemplary substituents include, but are notlimited to, alkyl, substituted alkyl, and where valence allows thosegroups recited above as exemplary substituents for substituted alkylgroups.

The term “cycloalkyl” refers to a fully saturated and partiallyunsaturated cyclic hydrocarbon group containing from 1 to 3 rings and 3to 8 carbons per ring. Exemplary such groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, etc. A cycloalkyl ring may have a carbonring atom replaced with a carbonyl group (C═O), as illustrated below.Cycloalkyl groups include such rings having a second or third ring fusedthereto that is a heterocyclo, heteroaryl, or aryl group, provided thatin such cases the point of attachment is to the cycloalkyl portion ofthe ring system. The term “cycloalkyl” also includes such rings having asecond or third ring attached to the ring or ring system in a spirofashion wherein the spiro ring is either a heterocyclo or carbocyclicring. “Substituted cycloalkyl” refers to a cycloalkyl group as definedabove having one or more substituents, preferably 1 to 4 substituents,more preferably 1 to 2 substituents, at any available point ofattachment on either the cycloalkyl ring and where valence allows on anyrings fused or attached thereto. Exemplary substituents include, but arenot limited to, alkyl, substituted alkyl, and those groups recited aboveas exemplary substituents for substituted alkyl groups.

Thus, as an illustration non-limiting examples of cycloalkyl rings mayinclude,

and the like.

The terms “heterocycle,” “heterocyclic” and “heterocyclo” refer to fullysaturated or partially unsaturated non-aromatic cyclic groups (forexample, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to16 membered tricyclic ring systems) which have at least one heteroatomin at least one carbon atom-containing ring. Each ring of theheterocyclic group containing a heteroatom may have 1, 2, 3, or 4heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfuratoms, where the nitrogen and/or sulfur heteroatoms may optionally beoxidized and the nitrogen heteroatoms may optionally be quaternized. Aheterocyclo ring may have a carbon ring atom replaced with a carbonylgroup (C═O), as illustrated above for cycloalkyl groups. Theheterocyclic group may be attached to the remainder of the molecule atany nitrogen atom or carbon atom of the ring or ring system.Additionally, the heterocyclo group may have a second or third ringattached thereto in a spiro or fused fashion, provided the point ofattachment is to the heterocyclo group. An attached spiro ring may be acarbocyclic or heterocyclic ring and the second and/or third fused ringmay be a cycloalkyl, aryl or heteroaryl ring. Exemplary monocyclicheterocyclic groups include azetidinyl, pyrrolidinyl, pyrazolinyl,imidazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl,tetrahydrofuryl, tetrahydropyranyl, thiamorpholinyl, and the like.

Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl,quinuclidinyl, benzopyrrolidinyl, benzopyrazolinyl, benzoimidazolidinyl,benzopiperidinyl, benzopiperazinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, dihydroisoindolyl and the like.

“Substituted heterocycle,” “substituted heterocyclic,” and “substitutedheterocyclo” refer to heterocycle, heterocyclic or heterocyclo groupssubstituted with one or more substituents, preferably 1 to 4substituents, more preferably 1 to 2 substituents, at any availablepoint of attachment to the heterocyclo ring and/or any ring fused orattached thereto in a spiro fashion. Exemplary substituents include, butare not limited to, alkyl, substituted alkyl, and those groups recitedabove as exemplary substituents for substituted alkyl groups.

The term “heteroaryl” refers to aromatic cyclic groups (for example, 5to 6 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 16membered tricyclic ring systems) which have at least one heteroatom inat least one carbon atom-containing ring. Each ring of the heteroarylgroup containing a heteroatom may have 1, 2, 3, or 4 heteroatomsselected from nitrogen atoms, oxygen atoms and/or sulfur atoms, wherethe nitrogen and/or sulfur heteroatoms may optionally be oxidized andthe nitrogen heteroatoms may optionally be quaternized. (The term“heteroarylium” refers to a heteroaryl group bearing a quaternarynitrogen atom and thus a positive charge.) The heteroaryl group may beattached to the remainder of the molecule at any nitrogen atom or carbonatom of the ring or ring system. Additionally, the heteroaryl group mayhave a second or third carbocyclic (cycloalkyl or aryl) or heterocyclicring fused thereto provided the point of attachment is to the heteroarylgroup.

Exemplary monocyclic heteroaryl groups include pyrazolyl, imidazolyl,triazolyl, oxazolyl, furyl, thiazolyl, isoxazolyl, thiazolyl, pyridyl

pyridazinyl

pyrimidinyl

pyrazinyl [i.e.,

triazinyl, and the like. Unless reference is made to a specific point ofattachment, e.g., as in pyrid-2-yl, pyridazin-3-yl, it is intended thatsuch heteroaryl groups can be bonded to another moiety at any availablepoint of attachment.

Exemplary bicyclic heteroaryl groups include benzothiazolyl,benzoxazolyl, benzoxadiazolyl, benzothienyl, quinolinyl, chromenyl,indolyl, indazolyl, isoquinolinyl, benzimidazolyl, benzopyranyl,benzofuryl, benzofurazanyl, benzopyranyl, cinnolinyl, quinoxalinyl,pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),, triazinylazepinyl, andthe like.

“Substituted heteroaryl” refers to heteroaryl groups substituted withone or more substituents as valence allows, preferably 1 to 3substituents, more preferably 1 to 2 substituents, at any availablepoint of attachment to the heteroaryl ring and/or any ring fusedthereto. Exemplary substituents include, but are not limited to, alkyl,substituted alkyl, and those groups recited above as exemplarysubstituents for substituted alkyl groups.

When reference is made to an optionally-substituted, specifically-namedaryl, heteroaryl, cycloalkyl, or heterocyclo ring, the optionalsubstituents may be selected as valence allows from the groups recitedabove for the genus of rings of which the specifically-named group is amember. For example, “optionally-substituted phenyl” includesunsubstituted phenyl rings as well as phenyl rings containing one ormore substituents selected from those recited above for aryl groups.“Optionally-substituted pyridyl, pyridazinyl, pyrimidinyl, andpyrazinyl,” includes unsubstituted pyridyl, pyridazinyl, pyrimidinyl,and pyrazinyl rings, as well as such rings containing one or moresubstituents selected from those recited above for heteroaryl groups.

The term “optionally substituted oxadiazolyl” as used herein is intendedto refer to the group,

wherein R_(j) is selected from a substituent recited above forsubstituted heteroaryl groups.

The term “quaternary nitrogen” refers to a tetravalent positivelycharged nitrogen atom including, for example, the positively chargednitrogen in a tetraalkylammonium group (e.g., tetramethylammonium,N-methylpyridinium), the positively charged nitrogen in protonatedammonium species (e.g., trimethyl-hydroammonium, N-hydropyridinium), thepositively charged nitrogen in amine N-oxides (e.g.,N-methyl-morpholine-N-oxide, pyridine-N-oxide), and the positivelycharged nitrogen in an N-amino-ammonium group (e.g., N-aminopyridinium).

The terms “halogen” or “halo” refer to chlorine, bromine, fluorineand/or iodine.

The term haloalkyl refers to an alkyl group having a single halosubstituent or multiple halo substituents forming, for example, groupssuch as a perfluoroalkyl group including trichloromethyl ortrifluoromethyl (CCl₃ or CF₃). A haloC₁-C₄alkyl refers to a C₁-C₄alkylhaving one or more halo substituents.

The term haloalkoxy refers to an alkoxy group as defined above whereinthe alkyl moiety has a single halo substituent or multiple halosubstituents forming, for example, groups such as a trifluoromethoxy. AhaloC₁-C₄alkoxy refers to a C₁-C₄alkoxy having one or more halosubstituents.

The term “saturated” when used herein is intended to refer to fullysaturated and partially saturated moieties, and conversely,“unsaturated” refers to fully unsaturated and partially unsaturatedmoieties.

When a functional group is termed “protected”, this means that the groupis in modified form to mitigate, especially preclude, undesired sidereactions at the protected site. Suitable protecting groups for themethods and compounds described herein include, without limitation,those described in standard textbooks, such as Greene, T. W. et al.,Protective Groups in Organic Synthesis, Wiley, N.Y. (1999).

The term “selective” as used herein with reference to the capability ofthe claimed compounds to inhibit p38 activity means that the compound inquestion has a level of activity as measured in enzyme assays forinhibiting the p38 α/β kinase that is significantly greater than theactivity of the compound in inhibiting a plurality of other kinasesfalling within families throughout the human kinome. The term“significantly greater activity” includes the activity of at least onecompound having about 500-fold or more greater activity for inhibitingp38α/β enzyme as compared with the activity of the compound ininhibiting other kinases, for example, as compared with the activity ofthe compound in inhibiting about twenty-five or more other kinases, inanother example, as compared with about fifty or more other kinases, andin yet another example, as compared with about 100 or more otherkinases. Thus, a selective p38 inhibitor as defined herein according toone embodiment will inhibit the α-isoform of the p38 kinase, theβ-isoform of the p38 kinase, and/or both the α and β forms of the p38kinase, at least 500 times greater than it will inhibit any one of aplurality of other kinases. Thus, for example, considering an embodimentinvolving comparison with a sample of twenty-five other kinases, p38selective compounds will have 500 times greater activity in inhibitingp38α/β kinase as compared with any one of each of the twenty-five otherkinases considered individually (e.g., in a one-on-one comparison). Inanother embodiment of the invention, compounds are provided having atleast about 1,000-fold greater activity for inhibiting p38 α/β kinase ascompared with other kinases, for example, as compared with abouttwenty-five or more, about fifty or more, and in yet another example, ascompared with about 100 or more other kinases. In yet another embodimentof the invention, compounds are provided having at least about5,000-fold greater activity for inhibiting p38 α/β kinase as comparedwith other kinases, for example, as compared with about twenty-five ormore other kinases, as compared with about fifty or more other kinases,and in yet another example, as compared with about 100 or more otherkinases. The term “highly selective” as used herein means the compoundin question has at least about 10,000 fold greater activity forinhibiting the p38 α/β kinase enzyme as compared with at least thirtyother kinases, more preferably, as compared with at least about fifty ormore other kinases. When reference is made herein to “other kinases”,applicant intends to refer to kinases known in the field other than thep38 α/β kinases. For example, various known kinases and kinase familiesother than the 38 α/β kinase are identified in WO 02/062804, and inManning, G. et al., The Protein Kinase Complement of the Human Genome,Science (Washington, D.C., United States) (2002), 198(5600), at pp.1912-1916, 1933-1934, which is incorporated herein by reference. “Otherkinases” as identified therein thus may include, without limitation, oneor more kinases chosen from the following kinases and/or kinasefamilies: CaMK1, CaMK2, CDK, DAPK, EMT, FGF, FMS, GSK3, LCK, PDGF-R,PKA, PCK, RAF, RIPK, LIMK-1, SYK, Met, PAK-4, PAK-5, ZC-1, STLK-2,DDR-2, Aurora 1, Aurora 2, Bub-1, PLK, Chk1, Chk2, HER2, JAK, raf1,MEK1, EGF-R, RSK/RSK, IGF-R, IRAK, VEGF-R, P13K, PDK, HIPK, STKR, BRD,Wnk, NKF3, NKF4, NKF5, weel kinase, Src, Abl, ILK, MK-2, IKK-2, RIPK,Cdc7, Ste11, Ste20, Ste7, Tec, Trk, and/or Nek, and so forth. The aboveis an exemplary, non-limiting list of other kinases. Manning identified518 protein kinases, and applicant intends to incorporate each one ofthese 518 protein kinases other than the p38 kinase in the definition ofthe term “other kinases” as used herein.

There are many enzyme assays known in the field that may be used tomeasure the levels of activity to determine selectivity. Applicant hasdescribed certain enzyme assays below but does not intend to be limitedto use of these specific assays with regard to the definition ofselectivity herein.

Unless otherwise indicated, a heteroatom with an unsatisfied valence isunderstood to have hydrogen atoms sufficient to satisfy the valences, asone skilled in the field will appreciate.

The compounds of formula I may form salts which are also within thescope of this invention. Reference to a compound of the formula I hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic and/orbasic salts formed with inorganic and/or organic acids and bases. Inaddition, when a compound of formula I contains both a basic moiety,such as but not limited to a pyridine or imidazole, and an acidic moietysuch as but not limited to a carboxylic acid, zwitterions (“innersalts”) may be formed and are included within the term “salt(s)” as usedherein. Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts may also beuseful, e.g., in isolation or purification steps which may be employedduring preparation. Salts of the compounds of the formula I may beformed, for example, by reacting a compound I with an amount of acid orbase, such as an equivalent amount, in a medium such as one in which thesalt precipitates or in an aqueous medium followed by lyophilization.

The compounds of formula I which contain a basic moiety, such as but notlimited to an amine or a pyridine or imidazole ring, may form salts witha variety of organic and inorganic acids. Exemplary acid addition saltsinclude acetates (such as those formed with acetic acid or trihaloaceticacid, for example, trifluoroacetic acid), adipates, alginates,ascorbates, asparates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochloride, hydrobromides,hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates),lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g.,2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates,persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

The compounds of formula I which contain an acidic moiety, such as butnot limited to a carboxylic acid, may form salts with a variety oforganic and inorganic bases. Exemplary basic salts include ammoniumsalts, alkali metal salts such as sodium, lithium and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases (for example, organic amines) such as benzathines,dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glycamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl halides (e.g. methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug” as employed herein denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of theformula I, or a salt and/or solvate thereof. Solvates of the compoundsof formula I include, for example, hydrates.

Compounds of the formula I, and salts thereof, may exist in theirtautomeric form (for example, as an amide or imino ether). All suchtautomeric forms are contemplated herein as part of the presentinvention.

All stereoisomers of the present compounds (for example, those which mayexist due to asymmetric carbons on various substituents), includingenantiomeric forms and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers(e.g., as a pure or substantially pure optical isomer having a specifiedactivity), or may be admixed, for example, as racemates or with allother, or other selected, stereoisomers. The chiral centers of thepresent invention may have the S or R configuration as defined by theIUPAC 1974 Recommendations. The racemic forms can be resolved byphysical methods, such as, for example, fractional crystallization,separation or crystallization of diastereomeric derivatives orseparation by chiral column chromatography. The individual opticalisomers can be obtained from the racemates by any suitable method,including without limitation, conventional methods, such as, forexample, salt formation with an optically active acid followed bycrystallization.

All configurational isomers of the compounds of the present inventionare contemplated, either in admixture or in pure or substantially pureform. The definition of compounds of the present invention embraces bothcis (Z) and trans (E) alkene isomers, as well as cis and trans isomersof cyclic hydrocarbon or heterocyclo rings.

When reference is made herein to a compound of formula (I) herein, thisis intended to refer to each compound of formula (I), and each salt,prodrug, solvate, or isomer thereof, alone or in combination with othercompounds of formula (I), other salts, prodrugs, solvates, or isomers ofcompounds of formula (I), or other compounds not of formula (I), withoutlimitation to the manner in which said compound of formula (I), or salt,prodrug, solvate, or isomer thereof is made or formed, for example,whether existing in a pure form, isolated form, crude form, togetherwith one or more excipients or impurities, existing in a solid or liquidform, in a pharmaceutical preparation before administration to apatient, as formed in the body of a patient after administration to apatient, and so forth.

Throughout the specification, groups and substituents thereof may bechosen to provide stable moieties and compounds.

ALTERNATE EMBODIMENTS

According to one aspect of the invention, there is provided a method ofmodulating a p38 kinase in a mammal comprising administering to themammal an amount of a compound of formula (I), effective for inhibitingp38 in a mammal, and there are provided compounds for formula (I), whichare advantageous, preferably which are selective, for inhibiting p38kinase.

One preferred aspect of the invention involves compounds of formula (I),

-   -   wherein G is phenyl;    -   R₁ is aryl, substituted aryl, heteroaryl, or substituted        heteroaryl;    -   R₂ is hydroxyl(alkyl), alkoxy(alkyl), haloalkyl, halogen,        cyanoalkyl, alkoxy, substituted alkoxy, or R_(2a), wherein        R_(2a) is C₁₋₆alkyl, amino, alkylamino, substituted alkylamino,        cycloamino, substituted cycloamino, and C₁₋₆alkyl substituted        with one to two of amino, alkylamino, substituted alkylamino,        cycloamino, and/or substituted cycloamino;    -   R₃ is hydrogen or methyl;    -   R₄ is hydrogen, C₁₋₄alkyl, halogen, trifluoromethyl,        trifluoromethoxy, or cyano;    -   R₅ is trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl or        substituted alkyl;    -   X is —(C═O)NH—, or is absent;    -   R₆ is hydrogen, alkyl or substituted alkyl, alkoxy or        substituted alkoxy, phenoxy or substituted phenoxy, cycloalkyl        or substituted cycloalkyl, heterocycle or substituted        heterocycle, aryl or substituted aryl, heteroaryl or substituted        heteroaryl; or where X is absent, R₆ can also be halogen, cyano,        trifluoromethyl, alkyl, amino, or alkylamino; or alternatively,        R₆ is joined together with a group R₅ on an adjacent carbon atom        to form an optionally-substituted, fused five to six membered        heterocyclic or carbocyclic ring; and    -   m is 0, 1, or 2.

Applicant excludes from the scope of the invention herein as well asfrom the scope of alternate embodiments of the claimed compounds herein,certain specific species of compounds, namely, (A) compounds having theformula (I), wherein R₁ is an optionally-substituted phenyl, pyridyl,pyridazinyl, pyrimidinyl, or pyrazinyl ring; R₂ is R_(2a); R₃ ishydrogen; R₄ is methyl; m is 0; and X—R₆ is —C(═O)NH(C₁₋₆alkyl),—C(═O)NH(cyclopropyl), or optionally-substituted oxadiazolyl;

-   -   (B) compounds having formula (Ix):

wherein

-   -   -   (i) simultaneously, R₃₀ is trifluoromethyl, R₂ is methyl, R₃            is hydrogen, R₄ is bromo, X—R₆ is hydrogen, R_(5b) is            hydrogen, and R_(5a) is methyl or

-   -   -   (ii) simultaneously, R₃₀ is hydrogen or methoxy, R₂ is            hydrogen or methyl, R₃ is hydrogen, R₄ is hydrogen, X—R₆ is            hydrogen, R_(5b) is hydrogen, and R_(5a) is trifluoromethyl;        -   (iii) simultaneously, R₃₀ is chloro, R₂ is hydrogen, R₃ is            hydrogen, R₄ is hydrogen, X—R₆ is cyano, R_(5b) is hydrogen,            and R_(5a) is SR₁₇ wherein R₁₇ is morpholinylalkyl;        -   (iv) simultaneously, R₃₀ is fluoro, R₂ is methyl, R₃ is            hydrogen, R₄ is hydrogen, X—R₆ is cyano, R_(5b) is hydrogen,            and R_(5a) is N-piperidinyl;        -   (v) simultaneously, R₃₀ is halogen, R₂ is hydrogen or            methyl, R₃ is hydrogen, R₄ is hydrogen, X—R₆ is cyano,            R_(5b) is hydrogen, and R_(5a) is heterocyclo or substituted            heterocyclo;        -   (vi) simultaneously, R₃₀ is chloro, R₂ is trifluoromethyl,            R₃ is hydrogen, R₄ is hydrogen, X—R₆ is SO₂NH(cycloalkyl),            and R_(5a) and R_(5b) are hydrogen;        -   (vii) simultaneously, R₃₀ is hydrogen, R₂ is            trifluoromethyl, R₃ is hydrogen, R₄ is hydrogen, X—R₆ is            hydrogen, R_(5b) is hydrogen, and R_(5a) is substituted            alkyl;        -   (viii) simultaneously, R₃₀ is hydrogen, R₂ is            trifluoromethyl, R₃ is hydrogen, R₄ is methyl, X—R₆ is            hydrogen, R_(5b) is —C(═ONH(alkyl), and R_(5a) is hydrogen;            and        -   (ix) simultaneously, R₃₀ is methoxy, R₂ is methyl, R₃ is            hydrogen, R₄ is methyl, X—R₆ is a bicycliheterocyclo(alkyl)            or bicyclicheteroaryl(alkyl), and R_(5a) and R_(5b) are            hydrogen; and

    -   (C) compounds having the formula (Iy),

-   -   -   (i) simultaneously, R₂ is hydrogen, R₃ is trifluoromethyl,            R₄ is bromo, X—R₆ is hydrogen, R_(5a) is trifluoromethyl,            and R_(5b) is bromo; and wherein (ii) R₂ is methyl, R₃ is            hydrogen, R₄ is hydrogen, X—R₆ is cyano, R_(5a) is alkoxy,            and R_(5b) is hydrogen.

According to another aspect of the invention, there are providedcompounds of formula (I) herein, and methods of administering compoundsas defined in formula (I), for modulating the activity of p38 kinase ina patient, and/or for treating p38 associated-conditions in a patient,wherein R₁ in formula (I) is selected from:

-   -   R₃₀, R₃₁, R₃₂, R₃₃ and R₃₄ are selected from hydrogen, halogen,        cyano, trifluoromethyl, trifluoromethoxy, C₁₋₄alkyl,        O(C₁₋₄alkyl), nitro, and/or SO₂CH₃;    -   R₅₀ is hydrogen, alkyl, or arylalkyl; and n is at each        occurrence independently selected from 0-3; and/or        pharmaceutically-acceptable salts, prodrugs, solvates, isomers,        and/or hydrates thereof.

According to another aspect of the invention, there are providedcompounds of formula (I) herein, and methods of administering compoundsas defined in formula (I), for modulating the activity of p38 kinase ina patient, and/or for treating p38 associated-conditions in a patient,wherein:

-   -   R₁ is optionally-substituted aryl or heteroaryl;    -   R₂ is hydrogen, lower alkyl, halogen, haloalkyl,        trifluoromethyl, NH₂, NH(alkyl), NH(cycloalkyl), N(alkyl)₂, or        —CH₂—O—CH₃, wherein each of said alkyl and/or cycloalkyl groups        of R₂ are in turn optionally substituted with one to two of        hydroxy, alkoxy, heteroaryl, aryl, heterocyclo, cycloalkyl,        amino, and alkylamino;    -   R₃ is hydrogen or methyl;    -   R₄ is methyl or halogen;    -   X is —C(═O)NH— or is absent;    -   R₆ is lower alkyl or cyclopropyl, or when X is absent, R₆ is        optionally-substituted heteroaryl; and    -   m is 0 or 1; and/or pharmaceutically-acceptable salts, prodrugs,        solvates, isomers, and/or hydrates thereof.

According to another aspect of the invention, there are providedcompounds, and methods of administering compounds for modulating theactivity of p38 kinase in a patient, and/or for treating p38associated-conditions in a patient, wherein the compounds having theformula (I), above, wherein:

-   -   R₁ is optionally-substituted phenyl or pyridyl; and    -   R₂ is hydrogen, lower alkyl, halogen, haloalkyl,        trifluoromethyl, NH₂, NH(alkyl), NH(cycloalkyl), N(alkyl)₂, or        —CH₂—O—CH₃, wherein each of said alkyl groups of NH(alkyl),        and/or N(alkyl)₂, are in turn optionally substituted with one to        two of OH, O(C₁₋₄alkyl), imidazolyl, pyridyl, phenyl,        tetrahydrofuryl, NH₂, NH(alkyl), N(alkyl)₂, and/or        N-morpholinyl.

According to another aspect of the invention, there are providedcompounds, and methods of administering compounds for modulating theactivity of p38 kinase in a patient, and/or for treating p38associated-conditions in a patient, wherein the compounds having theformula (I), above, wherein:

-   -   R₃ is hydrogen or methyl;    -   R₄ is methyl or halogen;    -   X is —C(═O)NH— or is absent;    -   R₆ is lower alkyl or cyclopropyl, or when X is absent, R₆ is        optionally-substituted heteroaryl; and    -   m is 0 or 1; and/or pharmaceutically-acceptable salts, prodrugs,        solvates, isomers, and/or hydrates thereof.

According to another aspect of the invention, there are providedcompounds, and methods of administering compounds for modulating theactivity of p38 kinase in a patient, and/or for treating p38associated-conditions in a patient, wherein the compounds having theformula (I), above, wherein:

-   -   R₁ is optionally-substituted phenyl or pyridyl;    -   R₂ is hydrogen, lower alkyl, halogen, haloalkyl,        trifluoromethyl, NH₂, NH(alkyl), NH(cycloalkyl), N(alkyl)₂, or        —CH₂—O—CH₃, wherein each of said alkyl groups of NH(alkyl),        and/or N(alkyl)₂, are in turn optionally substituted with one to        two of OH, O(C₁₋₄alkyl), imidazolyl, pyridyl, phenyl,        tetrahydrofuryl, NH₂, NH(alkyl), N(alkyl)₂, and/or        N-morpholinyl;    -   R₃ is hydrogen or methyl (more preferably hydrogen);    -   R₄ is methyl or halogen (more preferably methyl);    -   X is —C(═O)NH— or is absent;    -   R₆ is lower alkyl or cyclopropyl, or when X is absent, R₆ is        optionally-substituted heteroaryl; and    -   m is 0; and/or pharmaceutically-acceptable salts, prodrugs,        solvates, isomers, and/or hydrates thereof.

According to another aspect of the invention, there are providedcompounds, and methods of administering compounds for modulating theactivity of p38 kinase in a patient, and/or for treating p38associated-conditions in a patient, wherein the compounds having theformula (I), above, wherein:

-   -   wherein G is phyenyl or pyridyl, R₅ is halogen, hydroxyl,        alkoxy, C₁₋₄alkyl, haloC₁₋₄alkyl, cyano, SO₂(C₁₋₄alkyl), nitro,        heteroaryl, substituted heteroaryl, —C(═O)NH(alkyl), —C(═O)NH₂,        and/or —C(═O)NH(cycloalkyl); wherein m is 0, 1, or 2; and/or        pharmaceutically-acceptable salts, prodrugs, solvates, isomers,        and/or hydrates thereof; excluding the specifically-identified        compounds and groups of compounds excluded from the scope of        formula (I), above.

According to another aspect of the invention, there are providedcompounds, and methods of administering compounds for modulating theactivity of p38 kinase in a patient, and/or for treating p38associated-conditions in a patient, wherein the compounds having theformula (I), above, R₃ is hydrogen and R₄ is methyl.

According to another aspect of the invention, there are providedcompounds, and methods of administering compounds for modulating theactivity of p38 kinase in a patient, and/or for treating p38associated-conditions in a patient, wherein the compounds having theformula (I), above, wherein G is phenyl and R₆ is a 5-memberedheteroaryl which may be optionally substituted.

According to another aspect of the invention, there are providedcompounds, and methods of administering compounds for modulating theactivity of p38 kinase in a patient, and/or for treating p38associated-conditions in a patient, wherein the compounds having theformula (I), above, wherein R₆ is selected from the group consisting of:

-   -   wherein R₂₀ is hydrogen, lower alkyl, C₃₋₆cycloalkyl, or phenyl,        more preferably wherein R₂₀ is methyl or ethyl.

According to another aspect of the invention, there are providedcompounds, and methods of administering compounds for modulating theactivity of p38 kinase in a patient, and/or for treating p38associated-conditions in a patient, wherein the compounds having theformula (I), above, wherein R₆ is selected from one of the heteroarylgroups recited immediately above, wherein X is absent or —C(═ONH—.

According to yet another aspect of the invention, there are providedcompounds according to the formula (I), above, wherein the variousgroups are as recited above for formula (I), but excluding (A) compoundshaving the formula (I), wherein R₁ is an optionally-substituted phenyl,pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl ring; R₂ is R_(2a); R₃is hydrogen; R₄ is methyl; m is 0; and X—R₆ is —C(═O)NH(C₁₋₆alkyl),—C(═O)NH(cyclopropyl), or optionally-substituted oxadiazolyl;

-   -   (B) compounds having formula (Ix):

wherein, simultaneously

-   -   -   (i) R₃₀ is selected from hydrogen, trifluoromethyl, halogen,            and methoxy;        -   (ii) R₂ is selected from hydrogen, methyl, and            trifluoromethyl;        -   (iii) R₃ is hydrogen;        -   (iv) R₄ is selected from hydrogen, bromo, and lower alkyl;        -   (v) X—R₆ is selected from hydrogen, cyano,            SO₂NH(cycloalkyl), bicyclicheterocyclo(alkyl) and            bicyclicheteroaryl(alkyl);        -   (vi) R_(5b) is selected from hydrogen and —C(═ONH(alkyl);            and        -   (vii) R_(5a) is selected from hydrogen, alkyl, substituted            alkyl, heterocyclo, or substituted heterocyclo,            trifluoromethyl, and SR₁₇ wherein R₁₇ is morpholinylalkyl;        -   X—R₆ is a, and R_(5a) and R_(5b) are hydrogen; and

    -   (C) compounds having the formula (Iy),

wherein

-   -   (i) simultaneously, R₂ is hydrogen or methyl, R₃ is hydrogen or        trifluoromethyl, R₄ is hydrogen or bromo, X—R₆ is hydrogen or        cyano, R_(5a) is trifluoromethyl or alkoxy, and R_(5b) is        hydrogen or bromo.

Various combinations of groups recited above may be selected to formfurther preferred and/or alternate embodiments of the invention.Additionally, other aspects of the invention may be apparent to oneskilled in the field considering the entire disclosure hereof, includingthe definitions, schemes, claims and examples herein.

METHODS OF PREPARATION

Compounds of Formula (I) may be prepared according to the followingSchemes and the knowledge of one skilled in the art. Variables set forthin the schemes, e.g., R₁ through R₈, can be selected from those groupsrecited in the claims herein, and Q may be selected from R₁ in theclaims. Solvents, temperatures, pressures, and other reaction conditionsmay readily be selected by one of ordinary skill in the art.

Compounds of formula (I) having the structure (Ia) can be preparedaccording to Scheme 1. Substituted pyrazoles (1-1) are eithercommercially available or can be prepared according to literatureprocedures. See, e.g., Europ. J. Org. Chem., 17, 2913-2920 (2002); WO01/46172; Heterocycles, 53, 2775-2780 (2000); J. Heterocyclic Chem., 37,175-180 (2000); Nippon Kagaku Kaishi, 10, 1144-1147 (1992); Pakistan J.Scientific and Industrial Research, 30, 1-4 (1987); J. HeterocyclicChem., 16, 657-660 (1979); J. Org. Chem., 21, 1240 (1956); and Joule etal., Heterocyclic Chemistry, 3d edition, Chapter 22. Hydrolysis of (1-1)gives the corresponding pyrazole acids (1-2), which can be coupled withaniline (1-4) or its salt form (such as HCl) to give compounds (Ia)under standard amine coupling conditions. Alternatively, the carboxylicacid moiety of (1-2) can be converted to the acid chloride (1-3), whichreacts directly with (1-4) in solvents such as DCM in the presence ofDIPEA (or other bases) to afford (Ia).

Compound (1-4) can be prepared as outlined in Scheme 1a by 1) reacting a3-nitro-benzoyl chloride (1a-1) (either commercially available or can beprepared by one skilled in the art) and an amine H₂N—R₆ in CH₂Cl₂ togive a nitro intermediate (1a-2); and 2) reducing (1a-2) underconditions such as hydrogen gas and a catalyst in a solvent to affordaniline(1-4). Its salt form can be prepared by reacting (1-4) with anappropriate acid (e.g., HCl).

Alternatively, Compound (1-4) can be prepared as outlined in Scheme 1b,by reacting a 3-amino-benzoic acid (1b-1) (either commercially availableor can be prepared by one skilled in the art) with the amine H₂N—R₆ inthe presence of a coupling agent, such as EDC/HOBt, in a suitablesolvent. Its salt form can be prepared by reacting (1-4) with anappropriate acid (e.g., HCl).

The compound of formula (I) having the structure (2-3) can be madethrough the alternate route outlined in Scheme 2. BOP coupling ofaniline (1-4) with lithium acctoacctate gives compound (2-1), which canbe reacted with DMF-DMA to give compound (2-2). Compound (2-2) can thenbe reacted with hydrazines to afford compound (2-3).

Pyrazoles bearing halo, amino, or alkylamino substitution at C5 can beprepared according to Scheme 3. Reaction of compound (3-1) (such as2-ethoxymethylene-malononitrile or 2-cyano-3-ethoxy-acrylic acid ethylester) with hydrazines gives pyrazoles (3-2), where the C4 position issubstituted by a electron withdrawing group (EWG) such as nitrile,methyl or ethyl ester. Conversion of the C5-amino group to the C5-bromogroup can be accomplished through reaction with tBuONO and copper (II)bromide. Hydrolysis of the ester or nitrile to the carboxylic acid,followed by amide bond formation, such as through reaction with HATU andthe aniline (1-4), gives compound (3-5). Substitution of the bromidewith nucleophiles (carbon, oxygen, sulfur, but in particularnitrogen-based nucleophiles) can be accomplished. Reaction of compounds(3-5) with primary or secondary amines in EtOH at elevated temperatureand pressure, under microwave irradiation gives amino-substitutedpyrazoles (3-6).

C5-amino substituted pyrazoles can alternately be prepared as shown inScheme 4. Aminopyrazoles (4-1) (generally prepared according to Scheme3) can be mono- or bis-alkylated through the reaction with alkyl halides(such as ethyl bromide) in the presence of a suitable base (such as NaH)to afford (4-2) or (4-3). Hydrolysis of the ester, followed by amidebond formation, such as through HATU coupling with (1-4), leads to theC5-alkylamino substituted pyrazoles (4-5) or (4-6).

Compounds of formula (5-6) can be prepared from commercially-availablecompound (5-1) as depicted in Scheme 5. Compound (5-1) can be reactedwith tert-butyl carbazate in an organic solvent, such as DCE, in thepresence of a base, such as triethylamine, to afford compound (5-2).Compound (5-2) can reacted with an acid, such as TFA, and neutralizedwith a base, such as aqueous sodium carbonate, to afford compound (5-3).Formation of the oxadiazole can be accomplished by heating compound(5-3) in triethyl orthoacetate to afford compound (5-4) that can bereduced with hydrogen in the presence of a suitable catalyst, such aspalladium on carbon, in a solvent, such as EtOH, to afford compound(5-5). Compound (5-5) can then be coupled to carboxylic acid (6) in asolvent such as DMF to provide compound (Ig). It should be understoodfrom the foregoing that in Shemes 1-4 and 6-8 herein, theoxadiazolyl-substituted aniline compound of formula (5-5) can besubstituted for the aniline of formula (1-4) and reacted with carboxylicacid pyrazoles, as in Schemes 1, 3 and 4, and/or treated as shown in theSchemes 2 and 8, to provide compounds of formula (I) and/or precursorsthereof.

Scheme 6 shows a process for making compounds of formula (6-7), whereinR₂ is alkyl, aminoalkyl, or substituted aminoalkyl. Ethylacetoacetate(6-1), for example, ethyl 3-oxobutanoate, can be reacted withmethanamine, such as dimethoxy-N-N-dimethylmethanamine (6-2) in solventto provide intermediate compound (6-3), which when reacted with anappropriate hydrazine, such as, for example, phenylhydrazine,pyridylhydrazine, etc., followed by addition of sodium hydroxide,provides intermediate sodium salt of formula (6-4). Reaction of sodiumsalt with acid such as HCl provides carboxylic acid of formula (6-5).The carboxylic acid can then be converted to the acid chloride uponreaction with sulfuryl chloride (see also scheme 1), in solvents such asDCM to provide compounds (6-6), which react with benzamide hydrochloride(1-4) (or alternatively compounds 5-5 as in scheme 5), in solvents suchas DCM in the presence of base such as DIPEA to provide compounds havingthe formula (6-7).

Scheme 7 reflects an alternate process following the general schematicof Scheme 6, but wherein R₂ is a directly-linked amine group, i.e.,cyano compound 7-1 is reacted with methanamine, such asdimethoxy-N-N-dimethylmethanamine (6-2) in solvent, followed by anappropriate hydrazine, such as, for example, phenylhydrazine,pyridylhydrazine, etc., in solvent, such as ethanol, followed byaddition of sodium hydroxide, to provides intermediate sodium salt offormula (7-2). The amino group of compound (7-2) which can be furtherelaborated to an alkylamine or substituted amine group R₂, applyingprinciples known in the field, and/or compound (7-2) can be incorporatedinto other schemes and processes disclosed herein. One skilled in thefield will appreciate whether use of amine-protecting groups for theamine of compound (7-2) may be appropriate given other reagents.

Diketene (8-1), wherein R_(2a) is hydrogen, alkyl, cycloamino,aminoalkyl (preferably wherein R_(2a) is hydrogen), and3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride can be reactedwith DIPEA in DCM at RT to provide compounds (8-3). Addition of DMF-DMAat RT and removal of DCM provides compounds (8-4), which upon reactionwith appropriate hydrazine (QNHNH₂), such as optionally-substitutedphenylhydrazine, pyridylhydrazine, etc., in solvent such as EtOH,provides compounds of formula (8-5) wherein R_(2a) is as defined above,preferably hydrogen.

In addition, other compounds of formula (I) may be prepared usingprocedures generally known to those skilled in the art. In particular,the following examples provide additional methods for the preparation ofthe compounds of this invention.

The invention will now be further described by the following workingexamples, which are preferred embodiments of the invention. HPLCpurifications were done on C18 reverse phase (RP) columns using waterMeOH mixtures and TFA as buffer solution. These examples areillustrative rather than limiting. There may be other embodiments thatfall within the spirit and scope of the invention as defined by theappended claims.

Step A:

To a solution 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester(0.25 g, 1.05 mmol) and copper (II) bromide (0.281 g, 1.26 mmol) inacetonitrile (2 mL) at 0° C. was added tert-butylnitrite (0.167 mL, 1.26mmol) dropwise. The reaction was warmed to RT over 2 hr, then stirredovernight at RT. The reaction was layered with EtOAC (8 mL) and washedwith 1N aq. HCl (2×3 mL), water (1×3 mL), brine (1×3 mL). The organicphase was dried over MgSO₄, filtered, and evaporated to afford (1A) as ayellow solid (0.304 g, 98%, 85% AP HPLC). HPLC ret. t. (min): 3.62, MW:295.13, LCMS[M+H]⁺=295.3.

Step B:

To a solution of compound (1A) (0.025 g, 0.085 mmol) in THF (1 mL) at 0°C. was added aq. NaOH (1 N, 0.25 mL, 0.25 mmol). The solution was warmedto RT overnight, then heated to 50° C. for 3-4 hr. The THF wasevaporated and the aqueous solution was acidified to approximately pH 3.The resulting precipitate was collected by filtration and allowed to airdry, affording (1B) as an off-white solid (0.015 g, 64%) HPLC ret. t.(min): 2.54, LCMS[M+H]⁺=267.1, 269.1.

Step C:

To 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid (1B) (0.25 g, 0.936mmol) was added thionyl chloride (3 mL). After stirring at RT for 1 hr,the thionyl chloride was evaporated. The resulting solid wasre-suspended in DCM (4 mL) and DIPEA (0.652 mL, 3.74 mmoL) and3-Amino-N-isoxazol-3-yl-4-methyl-benzamide (0.224 g, 1.03 mmol) wereadded. The reaction was stirred at RT overnight. The resulting solidthat formed was collected by filtration and washed with DCM to affordExample 1 as a yellow solid (0.415 g, 95%). HPLC ret. t. (min): 2.97,MW: 466.3, LCMS[M+H]⁺=466.1.

Examples 2-45

Compounds having the formula immediately below, wherein R₁, R₂, and R₆have the values reported in Table 1, were prepared following ananalogous procedure as described for Example 1.

TABLE 1 HPLC time Ex. No. R₁ R₂ R₆ (min.) MS (M⁺) 2

—CH₃

2.05 472.3 3

—CH₃

2.05 371.3 4

—CH₃

3.10 408.1 5

—CH₃

2.92 416.0 6

—CH₃

2.89 382.1 7

—CH₃

3.08 381.2 8

—CH₃

2.87 389.2 9

—CH₃

2.82 355.2 10

—CH₃

2.91 448.2 11

—CH₃

3.35 453.1 12

—CH₃

2.83 471.1 13

—CH₃

3.52 485.1 14

—CH₃

3.42 471.1 15

—CH₃

3.30 426.1 16

—CH₃

3.34 447.1 17

—CH₃

2.82 417.1 18

—CH₃

2.61 437.1 19

2.97 432.1 20

2.90 404.2 21

H

2.82 361.2 22 —CH₃ —CF₃

2.44 367.0 23

—CF₃

3.02 429.3 24

3.15 430.2 25

3.24 403.3 26

—CH₃

2.19 376.1 27

—CH₃

2.33 403.1 28

—CH₃

2.47 480.1 29

—CH₃

2.50 480.1 30

—CH₃

3.15 430.1 31

—CH₃

2.30 428.1 32

—CH₃

2.93 402.1 33

—CH₃

3.12 416.1 34

—CH₃

2.63 432.1 35

—CH₃

3.14 416.0 36

—CH₃

2.64 403.1 37

—CH₃

3.65 459.1 38

—CH₃

3.63 432.1 39

—CH₃

3.03 470.1 40

3.02 429.1 41

3.13 443.1 42

3.18 457.1 43

3.34 505.1 44

—H

2.49 379.2 45 —H —H

1.75 285.2 46

—CH₃

3.22 425.2 47

—CH₃

2.73 355.3

Examples 48-49

Compounds having the formula immediately below, wherein R₁, R₂, and R₆have the values reported in Table 2, were prepared following ananalogous procedure as described for Example 1.

TABLE 2 HPLC time Ex. No. R₁ R₂ R₆ (min.) MS (M⁺) 48 —CH₃ —CH₃

2.25 354.1 49 —CH₃ —CH₃

2.10 327.1

Example 50

Step A:

To a solution of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid ethylester (0.050 g, 0.169 mmol) in EtOH (1 mL) was added NaOEt (21 wt %,0.190 mL, 0.50 mmol). The solution was heated to 80° C. for 1.5 hr, thenthe EtOH was evaporated. The residue was taken up in water (2 mL), andextracted with EtOAc (3×3 mL). The extracts were washed with brine,dried over MgSO₄, filtered and concentrated to afford (50A) (0.0093 g,21%). HPLC ret. t. (min): 3.34, MW: 360.3, LCMS[M+H]⁺=261.

Step B:

To a solution of (50A) (0.009 g, 0.035 mmol) in THF (2 mL) was added aq.NaOH (1 N, 0.140 mL, 0.140 mmol). The reaction was stirred at RT for 2h, then heated to 50° C. and stirred overnight. The THF was evaporated,additional NaOH (0.50 mL) was added and heating continued for anadditional 24 hr. The solution was acidified to pH2-3 and extracted withEtOAc. The extracts were washed with brine, dried over MgSO₄, filteredand concentrated to afford (50B) (0.009 g, (90% AP)) The material wasused without further purification. HPLC ret. t. (min): 2.69, MW: 232.2,LCMS[M+H]⁺=233.

Step C:

To a solution of (50B) (0.009 g, 0.035 mmol) in DMF (1 mL) was addedHATU (0.025 g, 0.056 mmol) and DIPEA (0.030 mL, 0.172 mmol). Afterstirring at RT for 45 min., 3-Amino-N-cyclopropyl-4-methyl-benzamidehydrochloride (0.013 g, 0.056 mmol) was added. The reaction was stirredat RT overnight, then heated to 65° C. for 5 hr. Water (2 mL) was addedand the product was extracted with ethyl acetate to afford a cruderesidue that was further purified by Prep HPLC to afford (50) anoff-white solid (0.0051 g, 36% over 2 steps). HPLC ret. t. (min): 2.90,MW: 404.5, LCMS[M+H]⁺=405.1.

Examples 51-116

The following examples shown in Table 3 were prepared in a manneranalogous to Examples 1 and 50.

TABLE 3 HPLC time Ex. No. Structure (min.) MS (M⁺) 51

2.61 437.1 52

2.90 404.2 53

3.02 429.3 54

3.12 417.2 55

3.23 445.2 56

2.99 432.1 57

2.82 417.1 58

3.46 373.2 59

2.86 362.1 60

3.04 347.1 61

3.14 346.1 62

3.12 345.1 63

3.05 346.1 64

4.22 558.3 65

3.13 445.2 66

3.11 482.2 67

3.35 489.2 68

3.25 455.2 69

3.28 374.2 70

3.30 354.2 71

3.36 342.2 72

3.42 324.2 73

3.31 334.3 74

3.46 340.1 75

3.35 306.2 76

430.12 1.37^(a) 77

402.10 1.31^(a) 78

416.18 1.32^(a) 79

403.06 1.38^(a) 80

417.08 1.44^(a) 81

431.09 1.48^(a) 82

404.36 1.77^(a) 83

403.10 1.43^(a) 84

434.16 1.28^(a) 85

421.18 1.35^(a) 86

448.11 1.34^(a) 87

420.18 1.26^(a) 88

430.12 1.37^(a) 89

402.10 1.31^(a) 90

416.18 1.32^(a) 91

403.06 1.38^(a) 92

377.10 1.47^(a) 93

417.08 1.44^(a) 94

431.09 1.48^(a) 95

404.36 1.77^(a) 96

403.10 1.43^(a) 97

434.16 1.28^(a) 98

421.18 1.35^(a) 99

448.11 1.34^(a) 100

420.18 1.26^(a) 101

430.12 1.37^(a) 102

434.16 1.37^(a) 103

421.18 1.43^(a) 104

448.18 1.41^(a) 105

420.14 1.34^(a) 106

330.22 1.25^(a) 107

356.25 1.36^(a) 108

383.19 1.40^(a) 109

396.24 1.34^(a) 110

434.16 1.37^(a) 111

421.18 1.43^(a) 112

448.18 1.41^(a) 113

420.14 1.34^(a) 114

330.22 1.25^(a) 115

356.25 1.36^(a) 116

383.19 1.40^(a)

It is noted that Examples 117-200 below are prophetic examples.

Example 117

Step A:

A suspension of 5-amino-3-methyl-1-phenyl-pyrazole-4-carboxylic acid inthionyl chloride is stirred at rt for 1.75 h. The mixture isconcentrated under reduced pressure and is dried in vacuo to obtain theabove acid chloride.

Step B:

Compound from step A is added to a solution of3-cyclopropylcarboxamido-6-methylaniline in DCM and pyridine at reducedtemperature. The cooling bath is removed after addition and the solutionis stirred at rt for 15 min. The reaction mixture is concentrated andthe residue diluted with 0.5 N aq. HCl solution. The precipitate issonicated for several min and filtered. The solid is washed with 0.5 Naq. HCl solution, satd. aq. HaHCO₃ solution, water and is dried toobtain Example 117.

Example 118

Step A:

Ethyl(ethoxymethylene)-cyanoacetate is was added in portions to asuspension of 2-fluorophenylhydrazine hydrochloride and triethyl aminein absolute EtOH. The mixture is stirred for 50 min, diluted with waterand extracted with EtOAc. The organic extracts are combined, washed withwater, brine, dried (Na2SO4), filtered, and concentrated under reducedpressure an in vacuo to obtain the above compound.

Step B:

A solution of compound from step A in THF: MeOH and 2.5 N aq. NaOHsolution is heated to 60° C. for 8 h. The mixture is concentrated underreduced pressure and acidified with 6 N aq. HCl solution at 0° C. Theprecipitated solid is collected by filtration, washed with water andDCM, and is dried to obtain the above acid.

Step C:

A solution of carboxylic acid from step B in thionyl chloride is stirredat rt for 2 h. The mixture is concentrated under reduced pressure and invacuo to obtain the above acid chloride.

Step D:

Compound from Step C is added to a solution of3-methylcarboxamido-6-chloro-aniline in DCM and pyridine at 0° C. Thecooling bath is removed after addition and the solution is stirred at rtfor 45 min. The reaction mixture is concentrated and the residue isdiluted with 0.5 N aq. HCl solution (8 mL). The precipitated solid issonicated for several min and filtered. The solid is washed with 0.5 Naq. HCl solution, satd. aq. NaHCO₃ solution, water and is dried in vacuoto obtain the above Example 118.

Example 119

Step A:

Phenyl hydrazine, ethyl (ethoxymethylene)-cyanoacetate, and absoluteEtOH are refluxed 1 hr. The reaction volume is reduced by one-half andcooled in ice, and the desired product is collected by filtration. Thefiltrate volume is further reduced, cooled, and then filtered to collectthe above compound.

Step B:

Compound from step A, THF, MeOH and 3N NaOH are combined and refluxed 4hrs. Most of solvent is removed by evaporation and the remainder isneutralized with 1 N HCl. The solid product is collected by filtration,washed, and is dried to give the above compound.

Step C: Example 119

Compound from Step B, thionyl chloride, THF and DMF are refluxedbriefly. The cloudy reaction solution is filtered through a medium glassfrit, evaporated, and the residue is triturated with 9:1 hexanes:diethylether to yield a product. This is redissolved into THF and was slowly isadded to a second reaction solution containing 3-amino-4-methylmethylbenzamide and pyridine in THF at 0 deg C. The reaction is allowedto stir overnight and reach rt. Reaction is evaporated and the productis washed with 1 N HCl, 1 N NaOH, and is dried to yield the aboveExample 119.

Example 120

Step A:

Ethyl(ethoxymethylene)cyanoacetate and 4-fluorophenylhydrazinehydrochloride are mixed in absolute EtOH at RT and triethylamine isintroduced via syringe dropwise. The mixture is stirred overnight,diluted with ether and filtered. The filtrate is diluted with EtOAc andis washed with water, brine, dried over Na₂SO₄, filtered, and isconcentrated under reduced pressure to obtain the above compound.

Step B:

A solution of compound from Step A in absolute EtOH and 3 N aq. NaOHsolution is refluxed for 2 h. The mixture is concentrated under reducedpressure and is taken up in water and is washed with DCM. The aqueouslayer is acidified with 6 N aq. HCl solution at 0° C., and theprecipitate is collected by filtration, is washed with water, and isdried to obtain the above acid.

Step C: Example 120

To a slurry of carboxylic acid from step B in DCM is added thionylchloride. After 10 min, DMF is added, then the solution is stirred atRT. The mixture is concentrated under reduced pressure to obtain aproduct. The product is slurred in DCM and cooled to 0° C. whereupon3-methylcarboxamido-6-chloroaniline is added and is followed by adropwise addition of a solution of pyridine in DCM over 15 min. Afterthe addition is complete, the cooling bath is removed and the solutionis stirred at rt for 30 min. The reaction mixture is concentrated andthe residue is treated with water and 1N aq. HCl. The resulting slurryis sonicated for several minutes, filtered, and is washed with 1 N aq.HCl solution, water and is dried in vacuo. The product is trituratedwith hot EtOAc, hot ether, then washed with acetonitrile and isdecolorized in MeOH using charcoal. The filtrate is concentrated and theresulting solid is recrystallized from MeOH/acetonitrile to afford theabove Example 120.

Examples 121-130

Examples 121 to 130, having the above formula wherein the variables R₁,R₃, R₄ and R₆ have the values shown in Table 4 are prepared followingthe procedures described in the preparation of the foregoing Examples117 through 120.

TABLE 4 Ex.# R₁ R₆ R₃ R₄ 121

—CH₃ —CH₃ —CH₃ 122

—CH₃ —CH₃ 123

—CH₃ —CH₃ 124

—CH₃ —CH₃ 125

—CH₃ —CH₃ —CH₃ 126

—CH₃ —H —Cl 127

—H —Cl 128

—H —Cl 129

—H —Cl 130

—CH₃ —H —Cl

Example 131

Step A:

To ethyl acetoacetate is added p-TsOH and DMF-DMA. The solution isheated at 100° C. for 2.5 hr, then cooled to RT. A distillationapparatus is attached and the product is purified by fractionaldistillation under vacuum to give (131A).

Step B:

To a solution of (131A) in EtOH is added pyridin-2-yl-hydrazine. Thesolution is heated to 65° C. for 3 h, then aq NaOH is added and thereaction is allowed to cool to RT overnight. The EtOH is evaporated andthe resulting aqueous solution is acidified to approximately pH 3. Theresulting precipitate is collected by filtration and allowed to air dry,affording (131B).

Step C:

To a solution of (131B) in NMP is added BOP, DIPEA and3-amino-5-chloro-N-cyclopropyl-4-methyl-benzamide hydrochloride. Thesolution is heated to 50° C. and allowed to stir overnight. The reactionis heated to 80° C. for an additional 4 hr. The solution is cooled to RTand water is added. The product is extracted with EtOAc to afford acrude product that can be further purified.

Examples 132-186

Examples 132-186, having the above formula of Core A or Core B, whereinthe variables R₁, R₂ and R₆ have the values shown in Table 5 can beprepared following the procedures described in the preparation ofExamples 117-120 and 131.

TABLE 5 Ex. No. Core R₁ R₂ R₆ 132 A

—CH₃

133 A

—CH₃

134 A

—CH₃

135 A

—CH₃

136 A

—CH₃

137 A

—CH₃

138 A

—CH₃

139 A

—CH₃

140 A

—CH₃

141 A

—CH₃

142 A

—CH₃

143 A

—CH₃

144 A

—CH₃

145 A

—CH₃

146 A

—CH₃

147 A

—CH₃

148 A

—NH₂

149 A

n-propyl —CH₃ 150 A

n-propyl

151 A

—CH₃

152 A

—CH₃

153 A

—CH₃

154 A

—CH₃

155 A

—CH₃

156 A

n-propyl n-propyl 157 A

n-propyl Et 158 A

n-propyl —CH₂—CH(CH₃)₂ 159 B

—CH₃

160 B

—CH₃

161 B

—CH₃

162 B

—CH₃

163 B

—CH₃

164 B

—CH₃

165 B

—CH₃

166 B

—CH₃

167 B

—CH₃

168 B

—CH₃

169 B

—CH₃

170 B

—CH₃

171 B

—CH₃

172 B

—CH₃

173 B

—CH₃

174 B

—CH₃

175 B

—NH₂

176 B

n-propyl —CH₃ 177 B

n-propyl

178 B

—CH₃

179 B

—CH₃

180 B

—CH₃

181 B

—CH₃

182 B

—CH₃

183 B

n-propyl n-propyl 184 B

n-propyl Et 185 B

n-propyl —CH₂—CH(CH₃)₂ 186 B

n-propyl Iso-Pr

Examples 187-190

Examples 187-190, having the above formula wherein the variables R₁, R₆and R₈ have the values shown in Table 6, can be prepared following theprocedures described in the previous examples and schemes.

TABLE 6 Ex. No. R₁ R₈ R₆ 187

Et Et 188

Et Et 189

Et Et 190

Et

Example 191

Step A:

To a rt solution of tert-butyl carbazate and triethylamine in DCE isadded a solution of 4-methyl-3-nitrobenzoyl chloride in DCE over 30minutes. After the addition is complete the resulting cloudy mixture isstirred at rt for 2 h then the mixture is successively washed with 10%aqueous citric acid and brine, then dried over anhydrous sodium sulfate.The solution is diluted with EtOAc, is filtered, and is concentrated invacuo. The mixture is diluted with hexanes and sonicated for a fewminutes, and the resulting precipitated solid is collected by vacuumfiltration and is dried in vacuo to afford the above compound (191A).

Step B:

Compound 191A from step A is added in portions to trifluoroacetic acidat 0° C. and the mixture is stirred at this temperature for 30 min andat rt for an additional 30 minutes. The mixture is then concentrated invacuo and the resulting white solid is partitioned between 2N aq sodiumcarbonate and EtOAc. The layers are separated and the aqueous portion isextracted with additional EtOAc, and the combined extracts are washedwith brine, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to yield the above compound 191B.

Step C:

A suspension of compound 191B in triethyl orthoacetate is heated to 100°C. giving a clear solution. After heating at this temperature for 2 h,the mixture is heated to 130° C. for an additional hour then cooled tort and heterogeneously concentrated in vacuo. The resulting residue isdissolved in EtOAc and washed with water and brine and is then driedover anhydrous sodium sulfate, is filtered, and concentrated in vacuo toafford compound 191C.

Step D:

To a suspension of compound 191C in EtOH is added 5% Pd/C and themixture is allowed to stir under an atmosphere of hydrogen at rt for 2h. The mixture is filtered through Celite and the resulting clearfiltrate is concentrated in vacuo and the residue is triturated withmethanol. Filtration and drying of the collected solid affords compound191D.

Step E: Example 191

A mixture of3,5-diMethyl-1-phenyl-1H-pyrazole-4-carboxylic acid,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and1-hydroxybenzotriazole in anhydrous DMF is reacted at rt for 1.5 h. Atthis time, aniline (191D) is added as solid and then is added DIPEA. Themixture is then heated at 60° C. for 16 h then the solution is dilutedwith water and allowed to cool to RT. The resulting solid is collectedby vacuum filtration and is dried in vacuo to afford Example 191.

Examples 192-97

Examples 192-97, having the above formula wherein the variables R₁ andR₂ have the values shown in Table 7, can be prepared following theprocedure described in the preparation of Example 191.

TABLE 7 Ex. No. R₁ R₂ 192

CH₃ 193

CH₃ 194

CH₃ 195

CH₃ 196

CH₃ 197

Examples 198-200

Compounds having the formula below for Examples 198-200, can be preparedfollowing the procedures described in the previous examples and schemes,wherein unspecified variables of R₁, R₂, and R₆ can be selected fromthose shown above in Tables 1-7 above.

Ex. Formula 198

199

200

1. A compound having the formula (I),

wherein G is phenyl; R₁ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,substituted cycloalkyl, heterocyclo or substituted heterocyclo, orC(═O)R₁₈; R₂ is hydrogen, hydroxyl(alkyl), alkoxy(alkyl), halogen,haloalkyl, cyanoalkyl, alkoxy, substituted alkoxy, or R_(2a), whereinR_(2a) is C₁₋₆alkyl, amino, alkylamino, substituted alkylamino,cycloamino, substituted cycloamino, or C₁₋₆alkyl substituted with one totwo of amino, alkylamino, substituted alkylamino, cycloamino, and/orsubstituted cycloamino; R₃ is hydrogen, haloalkyl, haloalkoxy, halogen,cyano, nitro, C₁₋₄alkyl, substituted C₁₋₄alkyl, NR₁₁R₁₂, or OR₁₁; R₄ ishydrogen, C₁₋₄alkyl, substituted C₁₋₄alkyl, halogen, haloalkyl,haloalkoxy, cyano, nitro, or OR₁₃; R₅ is at each occurrenceindependently selected from haloalkyl, haloalkoxy, cyano, nitro, alkylor substituted alkyl, alkenyl or substituted alkenyl, alkynyl orsubstituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycleor substituted heterocycle, aryl or substituted aryl, heteroaryl orsubstituted heteroaryl, OR₁₃, SR₁₃, S(═O)R₁₄, S(═O)₂R₁₄, P(═O)₂R₁₄,S(═O)₂OR₁₅, P(═O)₂OR₁₄, NR₁₃R₁₄, NR₁₃S(═O)₂R₁₅, NR₁₃P(═O)₂R₁₄,S(═O)₂NR₁₃R₁₄, P(═O)₂NR₁₃R₁₄, C(═O)OR₁₃, C(═O)R₁₃, C(═O)NR₁₃R₁₄,OC(═O)R₁₃, OC(═O)NR₁₃R₁₄, NR₁₃C(═O)OR₁₄, NR₁₆C(═O)NR₁₃R₁₄,NR₁₆S(═O)₂NR₁₃R₁₄, NR₁₆P(═O)₂NR₁₃R₁₄, NR₁₃C(═O)R₁₄, or NR₁₃P(═O)₂R₁₄; Xis —(C═O)NH—; R₆ is hydrogen, alkyl, alkoxy or substituted alkoxy,phenoxy or substituted phenoxy, cycloalkyl or substituted cycloalkyl,heterocycle or substituted heterocycle, aryl or substituted aryl,heteroaryl or substituted heteroaryl; or where X is absent, R₆ can alsobe selected from halogen, cyano, trifluoromethyl, alkyl, amino, and/oralkylamino; or alternatively, R₆ is joined together with a group R₅ onan adjacent carbon atom to form an optionally-substituted, fused five tosix membered heterocyclic or carbocyclic ring; R₁₁, R₁₂, R₁₃, R₁₄, R₁₅,R₁₆ and R₁₇ are independently at each occurrence selected from hydrogen,alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl,heterocycle or substituted heterocycle, aryl or substituted aryl, andheteroaryl or substituted heteroaryl, except R₁₅ is not hydrogen; R₁₈ ishydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl,alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl,heterocycle or substituted heterocycle, heteroaryl, or substitutedheteroaryl, aryl or substituted aryl; and m is 0, 1, 2 or 3; providedthat the following compounds are excluded: (A) compounds having theformula (I), wherein R₁ is an optionally-substituted phenyl, pyridyl,pyridazinyl, pyrimidinyl, or pyrazinyl ring; R₂ is R_(2a); R₃ ishydrogen; R₄ is methyl; m is 0; and X—R₆ is —C(═O)NH(C₁₋₆alkyl),—C(═O)NH(cyclopropyl), or optionally-substituted oxadiazolyl; (B)compounds having formula (Ix):

where (i) simultaneously, R₃₀ is trifluoromethyl, R₂ is methyl, R₃ ishydrogen, R₄ is bromo, X—R₆ is hydrogen, R_(5b) is hydrogen, and R_(5a)is methyl or

(ii) simultaneously, R₃₀ is hydrogen or methoxy, R₂ is hydrogen ormethyl, R₃ is hydrogen, R₄ is hydrogen, X—R₆ is hydrogen, R_(5b) ishydrogen, and R_(5a) is trifluoromethyl; (iii) simultaneously, R₃₀ ischloro, R₂ is hydrogen, R₃ is hydrogen, R₄ is hydrogen, X—R₆ is cyano,R_(5b) is hydrogen, and R_(5a) is SR₁₇ wherein R₁₇ is morpholinylalkyl;(iv) simultaneously, R₃₀ is fluoro, R₂ is methyl, R₃ is hydrogen, R₄ ishydrogen, X—R₆ is cyano, R_(5b) is hydrogen, and R_(5a) isN-piperidinyl; (v) simultaneously, R₃₀ is halogen, R₂ is hydrogen ormethyl, R₃ is hydrogen, R₄ is hydrogen, X—R₆ is cyano, R_(5b) ishydrogen, and R_(5a) is heterocyclo or substituted heterocyclo; (vi)simultaneously, R₃₀ is chloro, R₂ is trifluoromethyl, R₃ is hydrogen, R₄is hydrogen, X—R₆ is SO₂NH(cycloalkyl), and R_(5a) and R_(5b) arehydrogen; (vii) simultaneously, R₃₀ is hydrogen, R₂ is trifluoromethyl,R₃ is hydrogen, R₄ is hydrogen, X—R₆ is hydrogen, R_(5b) is hydrogen,and R_(5a) is substituted alkyl; (viii) simultaneously, R₃₀ is hydrogen,R₂ is trifluoromethyl, R₃ is hydrogen, R₄ is methyl, X—R₆ is hydrogen,R_(5b) is —C(═ONH(alkyl), and R_(5a) is hydrogen; and (ix)simultaneously, R₃₀ is methoxy, R₂ is methyl, R₃ is hydrogen, R₄ ismethyl, X—R₆ is a bicyclicheterocyclo(alkyl) orbicyclicheteroaryl(alkyl), and R_(5a) and R_(5b) are hydrogen; and (C)compounds having the formula (Iy),

wherein (i) simultaneously, R₂ is hydrogen, R₃ is trifluoromethyl, R₄ isbromo, X—R₆ is hydrogen, R_(5a) is trifluoromethyl, and R_(5b) is bromo;and wherein (ii) R₂ is methyl, R₃ is hydrogen, R₄ is hydrogen, X—R₆ iscyano, R_(5a) is alkoxy, and R_(5b) is hydrogen; and pharmaceuticallyacceptable salts and isomers thereof.
 2. A compound according to claim1, wherein R₁ is selected from:

R₃₀, R₃₁, R₃₂, R₃₃ and R₃₄ are selected from hydrogen, halogen, cyano,trifluoromethyl, trifluoromethoxy, C₁₋₄alkyl, O(C₁₋₄alkyl), nitro,and/or SO₂CH₃; and R₅₀ is hydrogen, alkyl, or arylalkyl; and n is ateach occurrence independently selected from 0-3; and/orpharmaceutically-acceptable salts, and isomers thereof.
 3. A compoundaccording to claim 1, wherein: R₁ is optionally-substituted aryl orheteroaryl; R₂ is hydrogen, lower alkyl, halogen, haloalkyl,trifluoromethyl, NH₂, NH(alkyl), NH(cycloalkyl), N(alkyl)₂, or—CH₂—O—CH₃, wherein each of said alkyl groups of NH(alkyl), and/orN(alkyl)₂, are in turn optionally substituted with one to two of OH,O(C₁₋₄alkyl), imidazolyl, pyridyl, phenyl, tetrahydrofuryl, NH₂,NH(alkyl), N(alkyl)₂, and N-morpholinyl; R₃ is hydrogen or methyl; R₄ ismethyl or halogen; X is —C(═O)NH—; R₆ is lower alkyl, cyclopropyl, oroptionally-substituted heteroaryl; and m is 0 or 1; and/orpharmaceutically-acceptable salts and isomers thereof.
 4. A compoundaccording to claim 1, having the formula,

wherein G is phenyl, R₅ is halogen, hydroxyl, alkoxy, C₁₋₄alkyl,haloC₁₋₄alkyl, cyano, SO₂(C₁₋₄alkyl), nitro, heteroaryl, substitutedheteroaryl, —C(═O)NH(alkyl), or —C(═O)NH(cycloalkyl); and/orpharmaceutically-acceptable salts and isomers thereof.
 5. The compoundof claim 1, wherein R₃ is hydrogen and R₄ is methyl.
 6. The compound ofclaim 1, wherein G is phenyl and R₆ is a 5-membered heteroaryl which maybe optionally substituted.
 7. The compound of claim 6, wherein R₂ islower alkyl, amino, or aminoalkyl, R₃ is hydrogen, R₄ is methyl orhalogen, and m is
 0. 8. The compound of claim 1, wherein R₆ is selectedfrom the group consisting of:

wherein R₂₀ is hydrogen, lower alkyl or phenyl.
 9. A compound accordingto claim 1, wherein: R₁ is optionally-substituted phenyl, pyridyl orpyradazinyl; R_(2a) is selected from the group consisting of amino,alkylamino, substituted alkylamino, cycloamino, substituted cycloamino,or C₁₋₆alkyl substituted with one to two of amino, alkylamino,substituted alkylamino, cycloamino, and/or substituted cycloamino; R₃ ishydrogen; R₄ is methyl; X is —C(═O)NH—; R₆ is lower alkyl, cyclopropyl,or an optionally-substituted pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, or oxadiazolyl; and m is 0 or 1; and/orpharmaceutically-acceptable salts and isomers thereof.
 10. The compoundof claim 9, wherein R₆ is selected from the group consisting of:

wherein R₂₀ is hydrogen, lower alkyl or phenyl.
 11. A compound accordingto claim 9, wherein R₁ is selected from:

R₃₀, R₃₁, R₃₂, R₃₃ and R₃₄ are selected from hydrogen, halogen, cyano,trifluoromethyl, trifluoromethoxy, C₁₋₄alkyl, O(C₁₋₄alkyl), nitro, andSO₂CH₃.
 12. A pharmaceutical composition comprising at least onecompound according to claim 1 and a pharmaceutically-acceptable carrieror diluent.
 13. A pharmaceutical composition comprising at least onecompound according to claim 4 and a pharmaceutically-acceptable carrieror diluent.
 14. A compound according to claim 1 wherein: R₁ is phenyloptionally substituted by fluoro or pyridyl optionally substituted byCF₃; R₂ is selected from the group consisting of H, —CH₃ and —NH₂; R₃ isH or —CH₃; R₄ is —CH₃ or Cl; and R₆ is selected from the groupconsisting of —CH₃, cyclopropyl and isoxazole.
 15. A compound accordingto claim 11 wherein: R₁ is

R₂ is —CH₃ or —NH₂; R₃ is hydrogen or —CH₃; R₄ is halo or —CH₃; m is 0;R₆ is cyclopropyl; and R₃₀, R₃₁, R₃₂, R₃₃ and R₃₄ are each independentlyselected from the group consisting of hydrogen, —CH₃, —OCH₂CH₃, halogen,cyano and trifluoromethyl.
 16. A compound according to claim 14 whereinR₁ is selected from the group consisting of:


17. A compound according to claim 16 wherein R₆ is cyclopropyl.